Defining miRNA targets: balancing simplicity with complexity.

M icro RNAs (miRNAs) are small RNAs that play an important role in the negative regulation of gene expression by suppressing protein translation. Animal genomes contain an abundance of small genes that produce regulatory RNAs of ≈22 nucleotides in length. The Ambros laboratory identified the first miRNAs in 1993 while characterizing a genetic locus involved in the control of developmental timing in Caenorhabditis elegans. 1 It has since been shown that these miRNAs are diverse in sequence and expression patterns and are evolutionarily widespread, suggesting that they may participate in a wide range of genetic and regulatory pathways. Since their initial discovery, thousands of articles have been published characterizing miRNA properties, defining their expression, and demonstrating function. miRNAs are initially transcribed as long primary miRNAs that are processed by the RNase III enzyme Drosha to generate stem-loop precursor miRNAs ≈70 nucleotides in length. 2 These precursors are exported into the cytoplasm, and subsequently, the cytoplas-mic enzyme Dicer cleaves the precursor miRNA to release the mature miRNA. 3 Binding of miRNA to an mRNA with Ago proteins inhibits protein translation. It is estimated that the human genome encodes ≈1500 miRNAs that are thought to regulate >30% of protein-coding genes. 4 Because interin-dividual variation of miRNA expression levels influences the expression of myriad miRNA target genes, these processes likely contribute to phenotypic differences and susceptibility to common and complex disorders. Consistent with the recent surge of studies characterizing the role of miRNAs in cellular function and disease relevance is the study by Ganesan et al 5 in the current issue of Circulation. This interesting study focused on miR-378 and its involvement in repressing cardiomyocyte hypertrophy. The study identified a relevant regulatory pathway, specifically mitogen-activated protein kinase, as a target of miR-378. Importantly, the study also clearly characterizes the underlying pathways that govern repression of the hypertrophic response by miR-378. A strength of this study is that the initial target was identified from a broader screen of synthetic miRNAs for the induction of cardiomyocyte hypertrophy and was not based only on prediction models. This initial description of miR-378 in cardiac hypertrophy supports several recent publications that demonstrate a role of miRNAs in cardiomyopathy 6,7 and mitogen-activated protein kinase 8,9 or specifically miR-378 in the cardiac regulation of apoptosis, ischemic heart disease, and mitochondrial function. The findings of Ganesan et al provide an interesting and important mechanistic link between an individual miRNA, a specific …